Gamma-interferon-inducible lysosomal thiol reductase diminishes cathepsin S expression and function (100.27)

Abstract

Abstract MHC class II-restricted processing requires protein degradation in the endosomal pathway for activation of CD4+ T cells. Gamma-interferon-inducible lysosomal thiol reductase (GILT) facilitates the processing of class II-restricted antigens by reducing protein disulfide bonds. Our previous work demonstrates that reductase active site mutants of GILT have diminished processing of precursor GILT to mature GILT, suggesting that GILT’s reductase active site may decrease the expression or activity of lysosomal proteases responsible for cleavage of GILT’s N- and C-terminal pro-peptides. Cathepsin S (CatS) is capable of processing precursor GILT to its mature form and mediates essential steps in class II-restricted processing, including proteolysis of large polypeptides and invariant chain cleavage. Therefore, we sought to determine whether GILT’s reductase activity regulates CatS expression and function. Our studies show GILT and CatS colocalize within lysosomes of murine B cells. GILT expression acts post-transcriptionally to decrease CatS steady state protein expression. GILT’s reductase active site is necessary for diminished CatS protein levels. However, GILT does not substantially alter the steady state protein expression of other lysosomal proteins, H2-M, H2-O or CatL. In addition, GILT expression decreases proteolysis of a CatS-selective substrate. Thus, GILT’s reductase activity is likely to fine tune class II-restricted antigen processing through decreasing CatS activity.